Autosomal dominant polycystic kidney disease (ADPKD) is among the most prevalent dominant human disorders, affecting between 1 in 1,000 and 1 in 3,000 individuals worldwide (Dalgaard, O. Z., 1957, Acta. Med. Scand. 158:1-251). The major manifestation of the disorder is the progressive cystic dilation of renal tubules (Gabow, P. A., 1990, Am. J. Kidney Dis. 16:403-413), leading to renal failure in half of affected individuals by age 50.
ADPKD-associated renal cysts may enlarge to contain several liters of fluid and the kidneys usually enlarge progressively causing pain. Other abnormalities such as pain, hematuria, renal and urinary infection, renal tumors, salt and water imbalance and hypertension frequently result from the renal defect. Cystic abnormalities in other organs, including the liver, pancreas, spleen and ovaries are commonly found in ADPKD. Massive liver enlargement occasionally causes portal hypertension and hepatic failure. Cardiac valve abnormalities and an increased frequency of subarachnoid and other intracranial hemorrhage have also been observed in ADPKD. Progressive renal failure causes death in many ADPKD patients and dialysis and transplantation are frequently required to maintain life in these patients. Although end-stage renal failure usually supervenes in middle age (ADPKD is sometimes called adult polycystic kidney disease), children may occasionally have severe renal cystic disease.
Although studies of kidneys from ADPKD patients have demonstrated a number of different biochemical, structural and physiological abnormalities, the disorder's underlying causative biochemical defect remains unknown. Biochemical abnormalities which have been observed have involved proteinsorting, the distribution of cell membrane markers within renal epithelial cells, extracellular matrix, ion transport, epithelial cell turnover, and epithelial cell proliferation. The most carefully documented of these findings are abnormalities in the composition of tubular epithelial cells, and a reversal of the normal polarized distribution of cell membrane proteins, such as the Na.sup.+ /K.sup.+ ATPase (Carone, F. A. et al., 1994, Lab. Inv. 70:437-448.).
As the name implies, ADPKD is inherited as an autosomal dominant disorder. Three distinct loci have been shown to cause phenotypically indistinct forms of the disease, with greater than 85-90% of disease incidence being due to mutations which map to the short arm of chromosome 16, as discussed below. Despite intensive investigation, the molecular defect responsible for ADPKD is not known.
In 1985 Reeders et al. (Reeders et al., Nature 317:542, 1985) carried out genetic linkage studies of a large number of ADPKD families and demonstrated that a gene on the short arm of chromosome 16 was mutated in most cases of ADPKD. This gene has been designated PKD1 by the Nomenclature Committee of the Human Gene Mapping Workshop and the Genome Data Base of the Welch library, John Hopkins University. Further linkage studies have identified a set of genetic markers that flank the gene-rich region containing the PKD1 gene (Reeders et al., 1988, Genomics 3:150; Somlo et al., 1992, Genomics 13:152; Breuning et al., 1990, J. Med. Genet. 27:603; Germino et al., 1990, Am. J. Hum. Genet. 46:925). These markers have been mapped by a variety of physical mapping techniques including fluorescent in situ hybridization and pulsed-field gel electrophoresis (Gillespie et al., 1990, Nucleic Acids Research 18:7071). It has been shown that the closest distal genetic marker (D16S259; on the telomeric side of the PKD1 locus) lies within 750 kb of the closest proximal genetic marker (D16S25; on the centromeric side of the PKD1 locus). The interval between the genetic markers has been cloned in a series of overlapping cosmid and bacteriophage genomic clones (Germino et al., 1992, Genomics 13:144), which contain the entire PKD1 interval, with the exception of two gaps of less than 10 kb and less than 50 kb. Restriction mapping of these clones has confirmed that the interval between the flanking genetic markers is 750 kb.
While genetic mapping studies such as these have begun to narrow the region within the human genome in which the gene responsible for ADPKD lies, there exist an estimated twenty or more genes within this 750 kb interval. Given the prevalence and severity of ADPKD, however, it is of great importance to eludicate which, if any, of these postulated genes corresponds to PKD1.